Platinum-based Nano-drug for Tumor Chemotherapy

Author:Wang Zi Gui

Supervisor:huang yu bin


Degree Year:2019





Tumors have become an important disease threatening human health.The main treatment methods include surgical resection,chemotherapy and radiotherapy.Regardless of whether it is administered before or after surgery,chemotherapy confers a significant benefit with control tumor.Cisplatin is an important member of chemotherapy drugs,but its range of application is seriously restricted by its toxic side effects and some drug resistance problems.Therefore,in order to solve the therapeutic bottleneck of cisplatin drugs,different kinds of platinum-containing compounds have appeared successively,such as carboplatin,oxaliplatin,etc.;Subsequently,different kinds of tetravalent platinum,such as tetravalent reductive platinum and tetravalent photosensitive platinum,have appeared one after another.These drugs,especially tetravalent platinum drugs,remain at a low level in their blood circulation time,tumor site accumulation and chemotherapy efficacy,although they maintain their inert characteristics without external stimuli and thus reduce side effects.Based on this,our work mainly uses different nano drug delivery systems to load tetravalent reductive platinum or tetravalent photosensitive platinum,aiming to explore the different forms of platinum-based nano-drug for tumor chemotherapy and diagnosis,and provide new treatment for chemotherapy.The article mainly includes the following four aspects:Firstly,using the properties and safety of mesoporous silica nanoparticles(MSN),the surface was modified with lactose(LA)and hydrophilic PEG,and MSN was conjugated hydrophobic Pt(IV)inside the particles.The prepared MSN-P/LA-Pt enhances the circulation time of the material in the body due to the presence of PEG,so that the platinum-based nanocarrier utilizes a sufficiently high permeability and retention(EPR)effect and LA enables the platinum-based nano drug to actively accumulate at the tumor site.At the same time,the dual protection of chemically bonded tetravalent platinum and MSN channels effectively avoids the systemic toxicity caused by the early release of platinum and the release of divalent platinum by reaction with active components in the blood.Both in vitro and in vivo experiments have demonstrated that MSN-P/LA-Pt has potential applications for liver cancer chemotherapy.Secondly,the amphiphilic polymer was prepared by ring-opening of AGE with mPEG.The reductive tetravalent platinum was conjugated to the side chain and the photosensitizer TPP was packaged to prepared PolyPt@TPP micelles.The material can be found by TEM When the platinum is released,the micelle structure is maintained,which can effectively improve the circulation of TPP in the body,and also solve the problem that TPP cannot produce active oxygen after the drug is released.At the same time,experiments such as endocytosis,toxicity,lysosomal labeling and reactive oxygen species test have proved that PolyPt@TPP has reached the goal of material design at the cell level.At the animal level,experiments have shown that PolyPt@TPP can effectively inhibit tumor growth under light stimulation,and its cure rate is as high as 66.7%.In addition,by comparison with other small molecule drugs such as cisplatin,it can be found that the PoyPt@TPP has lowest systemic toxicity.Then,using the photosensitive tetravalent platinum prodrug and norcantharidin to synthesize the polymer dual drug monomer,the polymer of the photoactivatable main chain dual drug was successfully synthesized from the monomer.The polymer can self-assemble to form nano micelles,which not only improves the circulation time of the drug in vivo,but also effectively reduces the poisonous side effects.It has been proved by experiments that the drug release rate can be effectively improved under illumination and stabilized in dark conditions.Western Blot experiments demonstrated the effect of materials on P-Akt protein,wich demonstrated the role of norcantharidin in inhibiting DNA repair of platinum damage.In vitro cell experiments show the effect of dual drug synergistic therapy.Tumor inhibition experiments in vivo were guided by drug CT-mediated imaging.Compared with the cisplatin group and the polymer nanomedicine group uder dark condition,the antitumor effect of DDP NP under light conditions was better and it had a cure rate of 75%and the quality of life of the mice was not affected.Finally,the anti-cancer activity,imaging and a good function of reversing drug resistance of Pt(Ⅳ)-Ⅰ were utilized.Through the bonding of Pt(Ⅳ)-Ⅰ and biotin to form Bio-Pt-I,it is suitable as a drug carrier with sustained release and reduction responsiveness.Features.It can be seen from the in vitro toxicity test of different kinds of cells that Bio-Pt-I has a good effect on a variety of cells,and still has a good effect on drug-resistant cells.The CT imaging effect in vivo shows that Bio-Pt-I has a clear outline of the imaging effect,which is better than Bio-Pt-Cl.Bio-Pt-I has a good inhibitory effect on tumor growth and achieved a cure rate of 40%toward PDX liver cancer model.For the established CDX A549 and A549/DDP durg resistant cell models,Bio-Pt-I has a good inhibitory effect on both tumors,and the cure rate of Bio-Pt-I against A549 group is 60%;As for A549/DDP,the cure rate reached 40%.